This is the new submission in response to an R21/R33 (TaPHIR) funding opportunity determining whether targeting a novel immune-inhibitory pathway can deplete latently HIV infected CD4 memory T cells in HIV virally suppressed patients. Although highly active antiretroviral therapy (HAART) can suppress HIV replication and significantly improve the long-term health of the patient, it is unable to permanently remove latent reservoirs of virus. Therefore, novel strategies are needed to specifically target and destroy latently infected cells. The T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a newly described immune checkpoint inhibitory receptor expressed on subsets of activated T cells, and natural killer (NK) cells and found highly expressed on tumor infiltrating lymph nodes. In our preliminary studies we find increased TIGIT and PD-1 expression on effector memory CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue indicating that the TIGIT pathway is active in the non-human primate model. Our ongoing studies, reveal strikingly, that dual blockade of TIGIT and PDL-1 restores HIV and SIV effector T cell function indicating that potent anti-viral responses following dual blockade may aid in the killing of HIV-infected latent cells following reactivation. With the development of (1) TIGIT and PDL-1 mAbs and an anti-retroviral therapy regimen that consistently and potently inhibits SIV replication, we propose to determine whether targeting the TIGIT and PDL-1 immune-inhibitory pathway can deplete latently HIV and SIV infected CD4 memory T cells and serve as a novel HIV eradication approach in shock and kill cure approach. In the R21 phase we propose to determine the ability of TIGIT and PDL-1 blockade to increase antiviral efficacy in vitro and deplete or inactivate HIV and SIV latently activated cells by enhancing anti-HIV and SIV CD8 T cell activity. In the R33 we will test the ability of TIGIT and PDL-1 mAbs to clear the latent reservoir during fully suppressive HAART in the SIV infected rhesus macaque model of HIV. These studies are the first steps towards a novel approach that will lead to a sustained cure or functional cure. Given our exciting preliminary data, research capabilities we expect to reach the milestones outlined in this project.